Oxygen toxicity in aerobic organisms has been widely studied. The enzyme SOD--superoxide dismutase--plays a significant role in the defense against such toxicity.
Superoxide radical (O.sub.2.sup.-) is generated in various biological reactions; this free radical anion is potentially damaging either because it is extremely reactive or because it can generate highly toxic species like OH. Superoxide dismutase catalyses the dismutation of O.sub.2.sup.- : EQU 2H.sup.+ +O.sub.2.sup.- O.sub.2.sup.- .fwdarw.H.sub.2 O.sub.2 +O.sub.2
In a mammalian cell, two types of SOD are found. One contains both copper and zinc and is located in the cytosol and periplasmic space of the mitochondria (CuZnSOD). The other enzyme contains manganese and is present in the matrix of the mitochondria (MnSOD). All normal mammalian cell types investigated contain these two types of the enzyme, except erythrocytes which lack MnSOD. However, in nearly all of the tumor systems studied so far, the level of, CuZnSOD and MnSOD activities were diminished. There are a few exceptions for CuZnSOD activity, but no exception has been found in the case of MnSOD activity. In many tumor samples, the MnSOD content is reduced to a level where it cannot be detected. Superoxide, on the other hand, is apparently still being generated in tumor mitochondria, and conceivably, the presence of this reactive species coupled with the relative lack of MnSOD could lead to changes in key subcellular structures due to the presence of oxygen derived chemical species. These changes may, in turn, contribute to the cancer phenotype.
The role of SOD in cancer has been the topic of a recent review in Oberley, L. W. and Buettner, G. R., The Role of Superoxide Dismutase in Cancer: A Review, Cancer Res. 39:1141-1149 (1979) and in 2 Oberley, L. W., Superoxide Dismutase, Chapter 6, (CRC Press 1982), both hereby incorporated by reference. SOD activities for numerous cancer types are specified.
Reduced MnSOD activity has been found in over fifty human, rat, mouse, spontaneous, transplanted virally-induced, chemically-induced, in vivo and in vitro tumors. In addition, both CuZnSOD and MnSOD activities in over thirty types of human tumors have been found to be less than those in control organs, Westman, N. G. and Marklund, S. L., Copper and Zinc-Containing Superoxide Dismutase and Manganese-Containing Superoxide Dismutase in Human Tissues and Human Malignant Tumors, Cancer Res. 41:2962(1981), hereby incorporated by reference. Thus, it has been demonstrated that loss of SOD activity is characteristic of a wide variety of human tumors and is not a phenomenon restricted to mouse and rat tumors. Examples of cancer types characaterized by low SOD activity levels include: Morris hepatomas, H6 hepatoma, Novikoff hepatoma, C3H carcinoma, Lewis lung carcinoma, Walker carcinoma, Mammary adenocarcinoma, Ehrlich ascites, EL-4 ascites, Guerin T.sub.R ascites, S91 melanoma, B16 melantic melanoma, Sarcoma 180, L1210 leukemia, L1210/6MP lymphoid leukemia, L1210/5FU lymphoid leukemia, P388 lymphoid leukemia, L1210/0 lymphoid leukemia, and Manning leukemia. This theory of excess free radicals with a deficiency of free radical scavengers in cancer cells has also been proposed by Georgieff, K. K., Free Radical Inhibitory Effect of Some Anticancer Compounds, Science 173:537-539 (1971), hereby incorporated by reference. Georgieff showed that various types of chemotherapeutic agents exhibit free radical inhibitory activity.
The present invention seeks to overcome the problems and disadvantages of the prior art. It has been discovered that copper complexes, which themselves act as O.sub.2.sup.- scavengers, allow the neoplastic cell to revert to its non-cancerous phenotype. These complexes also inhibit cancer cell growth in vivo, thereby prolonging the survival of tumor-bearing host organisms. Tumor metastasis is also reduced. The discovery is not only a significant advance but also an unexpected discovery in the art of treating cancer.